First, determine the false-negative rate of RT-PCR on the day of symptom onset and three days later; discuss with your colleagues if antibody testing for SARS-CoV-2 can be used in low prevalence areas; and detect SARS-CoV-2−reactive CD4 T cells in unexposed individuals.
Afterwards, use optical coherence tomography (OCT) in patients with COVID-19 and describe retinal changes; and correlate perforin+ NK cell number to disease severity in COVID-19 patients.
Finally, randomize patients with mild to moderate COVID-19 to receive lopinavir/r, arbidol (200 mg TID) or no antiviral medication as control; find out why the treatment of COVID-19 with lopinavir/r at the currently used dose is unlikely to be effective; and analyze a group of 177 pediatric patients and find out how many were hospitalized and/or critically ill.
Grifoni A, Weiskopf D, Ramirez SI, et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell 2020, https://doi.org/10.1016/j.cell.2020.05.015. Full-text: https://www.cell.com/cell/pdf/S0092-8674(20)30610-3.pdf
Cellular response is a major knowledge gap. This important study identified circulating SARS-CoV-2−specific CD8 and CD4 T cells in around 70 and 100% of 20 COVID-19 convalescent patients, respectively. CD4 T cell responses to the spike protein were robust and correlated with the magnitude of IgG titers. Of note, the authors detected SARS-CoV-2−reactive CD4 T cells in 40-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating seasonal coronaviruses and SARS-CoV-2.
Bordoni V, Sacchi A, Cimini E, et al. An inflammatory profile correlates with decreased frequency of cytotoxic cells in COVID-19. Clin Infect Dis. 2020 May 1. PubMed: https://pubmed.gov/32407466. Full-text: https://doi.org/10.1093/cid/ciaa577
The increase in inflammatory mediators is correlated with a reduction of innate and adaptive cytotoxic antiviral function. Authors found a lower perforin+ NK cell number in 7 intensive care unit (ICU) patients compared to 41 non-ICU patients, suggesting an impairment of the immune cytotoxic arm as a pathogenic mechanism.
Kucirka LM, Lauer SA, Laeyendecker O, et al. Variation in False-Negative Rate of Reverse Transcriptase Polymerase Chain Reaction–Based SARS-CoV-2 Tests by Time Since Exposure. Annals Int Med 2020, May 13. https://doi.org/10.7326/M20-1495. Full-text: https://www.acpjournals.org/doi/10.7326/M20-1495
The authors estimated the false-negative rate by day since infection, reviewing 7 studies with a total of 1,330 respiratory samples analyzed by RT-PCR. Over the 4 days before symptom onset, the rate decreased from 100% to 67%. On the day of symptom onset (day 5), the rate was 38%, decreased to 20% (day 8) and then began to increase again, from 21% (day 9) to 66% (day 21). If clinical suspicion is high, infection should not be ruled out on the basis of RT-PCR alone. The false-negative rate is lowest 3 days after onset of symptoms, or approximately 8 days after exposure.
Mathur F, Mathur S. Antibody Testing For Covid-19: Can It Be Used As A Screening Tool In Areas With Low Prevalence? American Journal of Clinical Pathology 2020, May 15. Full-text: https://academic.oup.com/ajcp/advance-article/doi/10.1093/ajcp/aqaa082/5837473
Answer is: probably no, because specificity is not 100%. Average sensitivity and specificity of FDA-approved antibody tests is 84.9% and 98.6%, respectively. Given the variable prevalence of COVID-19 (1%-15%) in different places, the positive predictive value can be statistically as low as 30% to 50% in areas with low prevalence.
Marinho PM, Marcos AAA, Romano AC, Nascimento H, Belfort R Jr. Retinal findings in patients with COVID-19. Lancet. 2020 May 12PubMed: https://pubmed.gov/32405105. Full-text: https://doi.org/10.1016/S0140-6736(20)31014-X
COVID-19 and the eye: Using optical coherence tomography (OCT) as a non-invasive imaging technique that is useful for demonstrating subclinical retinal changes, the authors describe their experience in 12 adult patients (9 were physicians). All patients showed hyper-reflective lesions at the level of the ganglion cell and the inner plexiform layers more prominently at the papillomacular bundle in both eyes.
Amir Qaseem A, Yost J, Etxeandia-Ikobaltzeta I, et al. Should Clinicians Use Chloroquine or Hydroxychloroquine Alone or in Combination With Azithromycin for the Prophylaxis or Treatment of COVID-19? Annals Internal Medicine May 13, 2020. Full-text: https://www.acpjournals.org/doi/10.7326/M20-1998
The answer is: no. These “Living Practice Points” From the American College of Physicians (based on an evidence review conducted on 17 April 2020) very clearly say that both drugs should not be used as prophylaxis or treatment of patients with COVID-19. In light of known harms and very uncertain evidence of benefit in patients with COVID-19, however, clinicians may treat hospitalized COVID-19–positive patients in the context of a clinical trial.
Schoergenhofer C, Jilma B, Stimpfl T, et al. Pharmacokinetics of Lopinavir and Ritonavir in Patients Hospitalized With Coronavirus Disease 2019 (COVID-19). Annals of Internal Medicine 12 May 2020. Full-text: https://www.acpjournals.org/doi/10.7326/M20-1550
Although lopinavir trough levels were approximately 2-fold higher in 8 COVID-19 patients than in HIV infected patients receiving the same dose, levels may be too low for COVID-19. Approximately 60- to 120-fold higher concentrations are required to reach the assumed EC50 at trough levels, making effective treatment of COVID-19 with lopinavir/r at the currently used dose unlikely.
Wang X, Cao R, Zhang H, et al. The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro. Cell Discov. 2020 May 2;6:28. PubMed: https://pubmed.gov/32373347. Full-text: https://doi.org/10.1038/s41421-020-0169-8
Among six anti-influenza drugs, only arbidol efficiently inhibited SARS-CoV-2 infection in cell experiments. Functionally, arbidol appeared to block virus entry by impeding viral attachment and release from the endolysosomes. However, higher dosages may be required to achieve therapeutic efficacy (800 mg?) than the current dose (200 mg, 3 times/day) as recommended by the Chinese Guidelines.
Li Y, Xie Z, Lin W, et al. Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/moderate COVID-19: an exploratory randomized controlled trial. Med (Cell Press) 2020. Full-text: https://www.immunology.ox.ac.uk/covid-19/covid-19-immunology-literature-reviews/efficacy-and-safety-of-lopinavir-ritonavir-or-arbidol-in-adult-patients-with-mild-moderate-covid-19-an-exploratory-randomized-controlled-trial
This study randomized a total of 86 patients with mild to moderate COVID-19 to receive lopinavir/r, arbidol (200 mg TID) or no antiviral medication (control). The primary endpoint, the rate of positive-to-negative conversion of SARS-CoV-2 nucleic acid, was similar between groups. There were no differences between groups in the secondary endpoints, the rates of antipyresis, cough alleviation, or improvement of chest CT at days 7 or 14. Again, dosage of arbidol may have been too low.
DeBiasi RL, Song X, Delaney M, et al. Severe COVID-19 in Children and Young Adults in the Washington, DC Metropolitan Region. J Pediatr. 2020 May 13. PubMed: https://pubmed.gov/32405091. Full-text: https://doi.org/10.1016/j.jpeds.2020.05.007
From 177 infected pediatric patients, 44 were hospitalized and 9 were critically ill. Of these, 6/9 were adolescents and young adults > 15 years of age. Although asthma was the most prevalent underlying condition overall, it was not more common among patients with severe disease. There were no significant differences in the presence of underlying conditions overall or any specific underlying diagnosis. Asthma exacerbation is not the primary determinant of more severe disease.